Division of Hematology-Oncology, Department of Internal Medicine, Biochemical Research Institution, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea.
Department of Biological Sciences, Pusan National University, Busan, Korea.
Cancer Res Treat. 2022 Oct;54(4):1256-1267. doi: 10.4143/crt.2021.944. Epub 2021 Dec 31.
Pegfilgrastim is widely used to prevent chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) in patients with diffuse large B-cell lymphoma (DLBCL). We investigated the predictive factors affecting CIN and FN incidence in patients with DLBCL receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy with pegfilgrastim and conducted experiments to find reason for the occurrence of CIN even when pegfilgrastim was used.
We reviewed the CIN and FN events of 200 patients with DLBCL. Based on these data, we investigate the association with predictive factor and the levels of granulocyte-colony stimulating factor (G-CSF) receptor signaling pathway markers (pSTAT3, pAKT, pERK1/2, pBAD, and CXCR4) in bone marrow (BM) samples isolated from patients with DLBCL.
FN was significantly associated with stage III/IV (hazard ratio [HR], 12.74) and low serum albumin levels (HR, 3.87). Additionally, patients with FN had lower progression-free survival (PFS; 2-year PFS, 51.1 % vs. 74.0%) and overall survival (OS; 2-year OS, 58.2% vs. 85.0%) compared to those without FN. The occurrence of CIN was associated with overexpression of G-CSF receptor signaling pathway markers, and expression levels of these markers were upregulated in BM cells co-cultured with DLBCL cells. The rate of neutrophil apoptosis was also higher in neutrophils co-cultured with DLBCL cells and was further promoted by treatment with doxorubicin.
Our findings suggest that high DLBCL burden may alter the BM environment and G-CSF receptor signaling pathway, even in chemotherapy-naïve state, which may increase CIN frequency during R-CHOP chemotherapy.
培非格司亭广泛用于预防弥漫性大 B 细胞淋巴瘤（DLBCL）患者接受利妥昔单抗、环磷酰胺、多柔比星、长春新碱和泼尼松（R-CHOP）化疗引起的化疗诱导性中性粒细胞减少症（CIN）和发热性中性粒细胞减少症（FN）。我们研究了影响接受培非格司亭的 R-CHOP 化疗的 DLBCL 患者 CIN 和 FN 发生率的预测因素，并进行了实验以寻找即使使用培非格司亭仍发生 CIN 的原因。
我们回顾了 200 例 DLBCL 患者的 CIN 和 FN 事件。基于这些数据，我们研究了与预测因素的相关性以及从 DLBCL 患者分离的骨髓（BM）样本中粒细胞集落刺激因子（G-CSF）受体信号通路标志物（pSTAT3、pAKT、pERK1/2、pBAD 和 CXCR4）的水平。
FN 与 III/IV 期（危险比[HR]，12.74）和低血清白蛋白水平（HR，3.87）显著相关。此外，与无 FN 患者相比，FN 患者的无进展生存期（PFS；2 年 PFS，51.1%vs.74.0%）和总生存期（OS；2 年 OS，58.2%vs.85.0%）较低。CIN 的发生与 G-CSF 受体信号通路标志物的过表达相关，并且这些标志物在与 DLBCL 细胞共培养的 BM 细胞中的表达水平上调。与 DLBCL 细胞共培养的中性粒细胞的凋亡率也较高，并且在用多柔比星处理后进一步促进。
我们的研究结果表明，高 DLBCL 负担可能改变 BM 环境和 G-CSF 受体信号通路，即使在化疗初治状态下，这可能会增加 R-CHOP 化疗期间 CIN 的频率。
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